This program is focusing on issues of detection, metabolism, and toxicity of polychlorinated biphenyls (PCBs). The research will provide a more compete picture of the risks PCBs have for humans, from their environmental detection and metabolism through their effects on hepatic initiation and promotion as well as their involvement in other toxic phenomena. The program consists of four projects (3 biomedical and one non-biomedical) and synthesis and administrative costs. One of the biomedical projects is investigating specific mechanisms of activation of PCBs to toxic metabolites within the cell and organism. Researchers are examining issues of metabolic activation of PCBs to electrophilic, genotoxic species in vivo. The target of these activated metabolites would be cellular nucleophilic sites in protein, RNA, and DNA. Metabolism of PCBs may also give rise to reactive oxygen species. Their presence and reaction products will also be determined in vivo models. The other two biomedical projects are investigating the mechanism of toxic effects of PCBs in specific cell types. In one project, researchers are attempting to determine the mechanisms(s) of toxicity of congeneric PCBs in endothelial cells in culture. The hypothesis being tested is that PCBs are atherogenic by causing a breakdown in endothelial barrier function. This results in the enhanced transfer of plaque-forming substances from the vessel lumen into the arterial wall. This project will examine the specific types of lesions caused by PCBs in monolayers of endothelial cells. The other project is focusing on mechanisms of hepatic tumor promotion by PCBs. Using the rat liver model, researchers are examining: if PCBs induce changes in cellular proliferation or oxidative DNA damage, if PCBs inhibit apoptosis, and the mechanism of any effects. In the non-biomedical project, researchers are developing optical sensing systems for the detection of PCBs. Investigators are first constructing plasmids that contain the bacterial bph operon, mammalian dioxin-responsive enhancers, and the luciferase gene, which is responsible for the generation of luminescence. Next cellular systems that will bioluminesce in the presence of PCBs after insertion of the engineered plasmids will be prepared. Finally, biosensors will be developed using these systems. The knowledge of the location and concentration of PCBs will allow a determination of the toxic potential at any given site. These projects are supported by two cores. The synthesis core project provides all the congeneric PCBs required by the research projects. The administrative core coordinates the research efforts through a monthly meeting of faculty, students and research staff, where new findings will be discussed and ideas and concepts tested. A regular seminar open to the public will be established to address environmental issues. This Program will proved for training of several pre- and postdoctoral students.